The microscopic studies described in this R03 application are aimed at investigating the role of the amygdala (AMYG) and limbic thalamus (L-THAL) in the pathophysiology of schizophrenia (SZ). Although the involvement of these corticolimbic regions is increasingly supported by recent brain imaging and postmortem studies, very little information is currently available regarding the nature of the abnormalities at the cellular and circuit levels. Moreover, virtually nothing is known as to whether abnormalities in AMYG and L-THAL coexist in individual patients and whether they may be inter-related. These regions receive massive projections from the anterior cingulate gyrus (ACG), in which abnormalities within intrinsic circuits have been shown in SZ. We hypothesize that altered ACG input could induce concurrent changes in AMYG and L-THAL, although these changes may be different in the two regions, based on differences on their respective connectivities and neurochemical characteristics. In order to test whether SZ-related abnormalities coexist in these two regions, we have collected whole AMYG and thalami from normal controls (CONs), SZs and bipolar disorder (BDs) patients matched for age, postmortem interval and gender. We have chosen to measure total neuronal numbers and densities of neurochemically identified neuronal subpopulations as indices for these abnormalities. In Specific Aim 1, we will test whether neuronal loss occurs in either or both regions in SZ. Using 3-dimensional optical disector methods, total neuronal numbers in various nuclear subdivisions of AMYG and L-THAL will be estimated in serial Nissi-stained sections. In Specific Aim 2, the hypothesis that only some, phenotypically distinct, neuronal subsets are affected in AMYG and L-THAL will be tested. Using irnmunocytochemical (ICC) localization of glutamate, glutamate amino decarboxylase (GAD), parvalbumin, calretinin, calbindin-D28k, somatostatin, cholecystokinin, corticotropin releasing factor, neuropeptide Y, and vasoactive intestinal peptide, the numerical densities of specific neuronal subpopulations in AMYG and L-THAL of CONs, SZs and BDs will be assessed by standard cell counting methods. In L-ThAL, the length density of fibers, for CCK, NPY and SM will also be measured. Correlations between measurements in AMYG and L-THAL in SZs, as well as in BDs, will be estimated in order to test whether abnormalities in AMYG and L-THAL coexist in SZ and/or BD. These proposed postmortem investigations have been designed to provide a neuropathological profile for each these two regions and disorders and to explore the possibility that changes noted in the AMYG and L-THAL might be inter-related. By addressing the question of cell loss both in terms of total neuronal population, and with respect to neurochemically distinct neuronal subgroups, these proposed studies will provide essential information regarding the role played by AMYG and L-THAL in the pathophysiology of SZ.